The Tumor Suppression Potential of NF-kappaB2 p100

描述（由申请人提供）：本项目的长期目标是了解NF-β 2基因的遗传改变如何导致肿瘤发生。NF-κ β 2基因编码约100 kDa（p100）的蛋白质，可通过其C-末端死亡结构域和/或lkappaB活性促进细胞凋亡。响应于某些信号，p100被加工以产生对应于p100的N-末端一半的52-kDa转录因子（p52）。在乳腺癌中已经观察到p52的异常激活。此外，NF-κ B2基因的C-末端缺失和重排在多种B细胞和T细胞淋巴瘤中反复发生。这些遗传改变的一个基本特征是产生具有致癌潜力的C-末端截短的NF-κ B2突变体和作为凋亡蛋白的p100失活。我们最近的工作表明，p100是一个重要的调节TNF-α和活化诱导的胸腺细胞凋亡，和肿瘤源性NF-κ B2突变p80 HT在细胞和动物的致癌活性的抑制剂。这些发现使我们假设p100是一种肿瘤抑制因子，促进细胞凋亡，并作为一种内置的防御对致癌突变的NF-κ B2和异常激活的p52。我们将在基于细胞和动物的系统中测试这一假设。在基于动物的研究中（目的1），我们将在淋巴细胞中靶向表达p80 HT或p52的转基因小鼠中建立p100作为淋巴瘤发生的肿瘤抑制因子;我们将在这些小鼠模型中检查NF-κ B2 p100基因单倍不足抑制肿瘤的可能性;将在E/mu-myc转基因小鼠中评估p100作为一般肿瘤抑制因子的潜力。在基于细胞的研究中（目标2），我们将使用骨髓细胞转化作为读数，以确定p100的抗肿瘤功能所必需的生化活性和p100抑制肿瘤转化的凋亡途径;我们将描述来自具有确定的NF-κ B的动物的淋巴细胞和淋巴瘤细胞中的凋亡反应，kappaB 2突变，以确定在分子水平上的缺陷，在细胞凋亡调控，与淋巴瘤的发生，我们将使用胸腺激活诱导的细胞凋亡作为一个模型，以描绘的分子机制p100作为一种凋亡蛋白。这些研究可能会定义一类新的肿瘤抑制因子，作为一种监视机制，对自己的基因致癌突变。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how genetic alterations of the NF-(B2 gene may lead to tumorigenesis. The NF-kappaBeta2 gene encodes a protein of approximately 100-kDa (p100) that can promote apoptosis via its C-terminal death domain and/or lkappaB activity. In response to certain signals, p100 is processed to generate a 52-kDa transcriptional factor (p52) corresponding to the N-terminal half of p100. Aberrant activation of p52 has been observed in breast cancers. Also, C-terminal deletions and rearrangements of the NF-kappaB2 gene occur recurrently in a variety of B- and T-cell lymphomas. A fundamental feature of these genetic alterations is the generation of C-terminally truncated NF-kappaB2 mutants with oncogenic potential and the inactivation of p100 as an apoptotic protein. Our recent work suggests that p100 is a crucial regulator of TNF-alpha- and activation-induced apoptosis in thymocytes, and an inhibitor of the oncogenic activity of the tumor-derived NF-kappaB2 mutant p80HT in cells and in animals. These findings lead us to hypothesize that p100 is a tumor suppressor that promotes apoptosis and acts as a built-in defense against oncogenic mutations of NF-kappaB2 and aberrant activation of p52. We will test this hypothesis in both cell- and animal-based systems. In animal-based studies (Aim 1), we will establish p100 as a tumor suppressor against lymphomagenesis in transgenic mice with targeted expression of p80HT or p52 in lymphocytes; we will examine the possibility that the NF-kappaB2 p100 gene is haplo-insufficient for tumor suppression in these mouse models; the potential of p100 as a general tumor suppressor will be assessed in E/mu-myc transgenic mice. In cell-based studies (Aim 2), we will use bone marrow cell transformation as readout to define the biochemical activity of p100 essential for its anti-oncogenic function and the apoptotic pathway through which p100 suppresses oncogenic transformation; we will characterize apoptotic responses in lymphocytes and lymphoma cells from the animals with defined NF-kappaB2 mutations to identify at molecular levels the defects in apoptosis regulation that are linked to lymphomagenesis; we will use thymic activation-induced apoptosis as a model to delineate the molecular mechanism for p100 as an apoptotic protein. These studies may define a new class of tumor suppressors that act as a surveillance mechanism against oncogenic mutations of their own genes.